Metal mediated intramolecular transformations of pyridine substrates

Nature continuously provides fascinating and complicated structures which offer synthetic chemists amazing opportunities for the design of new methods for the natural product synthesis. Nitrogen containing aza-heterocycles are of unparalleled importance in natural product, bioorganic and medicinal chemistry. Pyridine in particular is one of the most common aza-heterocycles encountered in natural products, medicinal and materials chemistry. Pyridine derivatives also server as precursors to functionalized piperidines, which are likewise common structural motifs in bioactive and functionalized materials. Thus developing synthetic methods suitable for the manipulation of pyridine ring systems remains an important objective in the organic chemistry community.

We approached this objective by two different routes. In the first method, we used the nucleophilicity of the benzylic position of the 4-alkyl pyridine substrates to engage in gold (I) catalyzed 5 or 6-endo dig cyclizations with attached alkynyl amide groups. Processing of the so formed cycloadducts under hydrolytic conditions then afforded substituted pyridines with functionalized lactams.

In the second approach, we investigated the feasibility of Pd-catalyzed cyclization of 3-substituted pyridines. It was envisioned that Pd(0) catalysts could react with alkyne substituents positioned along the pyridine periphery such that nucleophilic alkeynyl moiety would be generated. Activation of the pyridine by N-alkylation or acylation would then result in intramolecular cyclization. Rather than the desired reaction pathway, however, only products of alkyne hydroarylation were observed.